The Experts below are selected from a list of 18 Experts worldwide ranked by ideXlab platform

Leonard M Neckers - One of the best experts on this subject based on the ideXlab platform.

  • the benzoquinone Ansamycin 17 allylamino 17 demethoxygeldanamycin binds to hsp90 and shares important biologic activities with geldanamycin
    Cancer Chemotherapy and Pharmacology, 1998
    Co-Authors: Theodor W. Schulte, Leonard M Neckers
    Abstract:

    Purpose: Benzoquinone Ansamycins are antibiotics with anticancer potential. First described as tyrosine kinase inhibitors, they are now frequently used to target HSP90 chaperone function. While herbimycin A and geldanamycin (GA) have been widely used in preclinical studies, both drugs are poor candidates for clinical trials owing to their in vivo toxicity and lack of stability. We therefore examined the biologic effects of 17-allylamino-17-demethoxygeldanamycin (17-AG), an Ansamycin Derivative with lower in vivo toxicity than GA. Methods: Binding of 17-AG to HSP90 was studied in vitro using a GA-affinity beads competition assay. We analyzed the drug-induced destabilization of p185erbB2, Raf-1 and mutant p53 in SKBR3 breast cancer cells by Western blotting. The antiproliferative activities of 17-AG and GA were compared using the MTT assay. Results: We found that, in a similar manner to GA itself, 17-AG bound specifically to HSP90. It also led to degradation of the receptor tyrosine kinase p185erbB2, the serine/threonine kinase Raf-1 and mutant p53. Both GA and 17-AG displayed comparable antiproliferative effects in SKBR3 and MCF7 cells. Even though HSP90 binding by 17-AG was weaker than by GA, 17-AG and GA caused biologic effects in tumor cells at similar doses. Conclusion: 17-AG shares the important biologic features of its parent compound GA. Since 17-AG has a better toxicity profile than GA, it is an interesting candidate benzoquinone Ansamycin for clinical development.

  • the benzoquinone Ansamycin 17 allylamino 17 demethoxygeldanamycin binds to hsp90 and shares important biologic activities with geldanamycin
    Cancer Chemotherapy and Pharmacology, 1998
    Co-Authors: Theodor W. Schulte, Leonard M Neckers
    Abstract:

    Purpose: Benzoquinone Ansamycins are antibiotics with anticancer potential. First described as tyrosine kinase inhibitors, they are now frequently used to target HSP90 chaperone function. While herbimycin A and geldanamycin (GA) have been widely used in preclinical studies, both drugs are poor candidates for clinical trials owing to their in vivo toxicity and lack of stability. We therefore examined the biologic effects of 17-allylamino-17-demethoxygeldanamycin (17-AG), an Ansamycin Derivative with lower in vivo toxicity than GA. Methods: Binding of 17-AG to HSP90 was studied in vitro using a GA-affinity beads competition assay. We analyzed the drug-induced destabilization of p185erbB2, Raf-1 and mutant p53 in SKBR3 breast cancer cells by Western blotting. The antiproliferative activities of 17-AG and GA were compared using the MTT assay. Results: We found that, in a similar manner to GA itself, 17-AG bound specifically to HSP90. It also led to degradation of the receptor tyrosine kinase p185erbB2, the serine/threonine kinase Raf-1 and mutant p53. Both GA and 17-AG displayed comparable antiproliferative effects in SKBR3 and MCF7 cells. Even though HSP90 binding by 17-AG was weaker than by GA, 17-AG and GA caused biologic effects in tumor cells at similar doses. Conclusion: 17-AG shares the important biologic features of its parent compound GA. Since 17-AG has a better toxicity profile than GA, it is an interesting candidate benzoquinone Ansamycin for clinical development.

Theodor W. Schulte - One of the best experts on this subject based on the ideXlab platform.

  • the benzoquinone Ansamycin 17 allylamino 17 demethoxygeldanamycin binds to hsp90 and shares important biologic activities with geldanamycin
    Cancer Chemotherapy and Pharmacology, 1998
    Co-Authors: Theodor W. Schulte, Leonard M Neckers
    Abstract:

    Purpose: Benzoquinone Ansamycins are antibiotics with anticancer potential. First described as tyrosine kinase inhibitors, they are now frequently used to target HSP90 chaperone function. While herbimycin A and geldanamycin (GA) have been widely used in preclinical studies, both drugs are poor candidates for clinical trials owing to their in vivo toxicity and lack of stability. We therefore examined the biologic effects of 17-allylamino-17-demethoxygeldanamycin (17-AG), an Ansamycin Derivative with lower in vivo toxicity than GA. Methods: Binding of 17-AG to HSP90 was studied in vitro using a GA-affinity beads competition assay. We analyzed the drug-induced destabilization of p185erbB2, Raf-1 and mutant p53 in SKBR3 breast cancer cells by Western blotting. The antiproliferative activities of 17-AG and GA were compared using the MTT assay. Results: We found that, in a similar manner to GA itself, 17-AG bound specifically to HSP90. It also led to degradation of the receptor tyrosine kinase p185erbB2, the serine/threonine kinase Raf-1 and mutant p53. Both GA and 17-AG displayed comparable antiproliferative effects in SKBR3 and MCF7 cells. Even though HSP90 binding by 17-AG was weaker than by GA, 17-AG and GA caused biologic effects in tumor cells at similar doses. Conclusion: 17-AG shares the important biologic features of its parent compound GA. Since 17-AG has a better toxicity profile than GA, it is an interesting candidate benzoquinone Ansamycin for clinical development.

  • the benzoquinone Ansamycin 17 allylamino 17 demethoxygeldanamycin binds to hsp90 and shares important biologic activities with geldanamycin
    Cancer Chemotherapy and Pharmacology, 1998
    Co-Authors: Theodor W. Schulte, Leonard M Neckers
    Abstract:

    Purpose: Benzoquinone Ansamycins are antibiotics with anticancer potential. First described as tyrosine kinase inhibitors, they are now frequently used to target HSP90 chaperone function. While herbimycin A and geldanamycin (GA) have been widely used in preclinical studies, both drugs are poor candidates for clinical trials owing to their in vivo toxicity and lack of stability. We therefore examined the biologic effects of 17-allylamino-17-demethoxygeldanamycin (17-AG), an Ansamycin Derivative with lower in vivo toxicity than GA. Methods: Binding of 17-AG to HSP90 was studied in vitro using a GA-affinity beads competition assay. We analyzed the drug-induced destabilization of p185erbB2, Raf-1 and mutant p53 in SKBR3 breast cancer cells by Western blotting. The antiproliferative activities of 17-AG and GA were compared using the MTT assay. Results: We found that, in a similar manner to GA itself, 17-AG bound specifically to HSP90. It also led to degradation of the receptor tyrosine kinase p185erbB2, the serine/threonine kinase Raf-1 and mutant p53. Both GA and 17-AG displayed comparable antiproliferative effects in SKBR3 and MCF7 cells. Even though HSP90 binding by 17-AG was weaker than by GA, 17-AG and GA caused biologic effects in tumor cells at similar doses. Conclusion: 17-AG shares the important biologic features of its parent compound GA. Since 17-AG has a better toxicity profile than GA, it is an interesting candidate benzoquinone Ansamycin for clinical development.

C. Babin-chevaye - One of the best experts on this subject based on the ideXlab platform.

  • Interaction of Rifalazil with Oxidant-Generating Systems of Human
    2005
    Co-Authors: Polymorphonuclear Neutrophils, M. T. Labro, V. Ollivier, C. Babin-chevaye
    Abstract:

    It is well acknowledged that Ansamycins display immunosuppressive and anti-inflammatory properties in vitro and in vivo. Rifalazil, a new Ansamycin Derivative, has not been studied in the context of inflammation. In particular, there are no data on the possible interference of rifalazil with oxidant production by phagocytes. We have compared the antioxidant properties of rifalazil to those of rifampin, a drug well known in this context, by using cellular and acellular oxidant-generating systems. Oxidant production by polymorphonuclear neutrophils was measured in terms of cytochrome c reduction, lucigenin-amplified chemiluminescence (Lu-ACL), and the 2,7-dichlorofluorescin diacetate H2 (DCFDA-H2) technique (intracellular oxidant production). Rifalazil impaired O2 production in a concentration-dependent manner, with 50 % inhibitory concentrations (IC50) (concentrations which inhibit 50 % of the response) of 5.4 (30 and 60 min of incubation) and 6.4 (30 min) mg/liter, respectively, for phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. In agreement with the published fMLP-like activity of rifampin, the inhibitory effect of rifampin was significantly greater for fMLP (IC50 of 5.6 mg/liter) than for PMA (IC50 of 58 mg/liter) stimulation. Alteration of intracellular oxidant production was also observed with IC50 values similar to those obtained by the cytochrome assay. In addition, rifalazil and rifampin (>25 mg/liter) scavenged O

Babin-chevaye C. - One of the best experts on this subject based on the ideXlab platform.

  • Interaction of Rifalazil with Oxidant-Generating Systems of Human Polymorphonuclear Neutrophils
    American Society for Microbiology, 2005
    Co-Authors: Labro M. T., Babin-chevaye C.
    Abstract:

    It is well acknowledged that Ansamycins display immunosuppressive and anti-inflammatory properties in vitro and in vivo. Rifalazil, a new Ansamycin Derivative, has not been studied in the context of inflammation. In particular, there are no data on the possible interference of rifalazil with oxidant production by phagocytes. We have compared the antioxidant properties of rifalazil to those of rifampin, a drug well known in this context, by using cellular and acellular oxidant-generating systems. Oxidant production by polymorphonuclear neutrophils was measured in terms of cytochrome c reduction, lucigenin-amplified chemiluminescence (Lu-ACL), and the 2′,7′-dichlorofluorescin diacetate H(2) (DCFDA-H(2)) technique (intracellular oxidant production). Rifalazil impaired O(2)(−) production in a concentration-dependent manner, with 50% inhibitory concentrations (IC(50)) (concentrations which inhibit 50% of the response) of 5.4 (30 and 60 min of incubation) and 6.4 (30 min) mg/liter, respectively, for phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. In agreement with the published fMLP-like activity of rifampin, the inhibitory effect of rifampin was significantly greater for fMLP (IC(50) of 5.6 mg/liter) than for PMA (IC(50) of 58 mg/liter) stimulation. Alteration of intracellular oxidant production was also observed with IC(50) values similar to those obtained by the cytochrome assay. In addition, rifalazil and rifampin (≥25 mg/liter) scavenged O(2)(−), as demonstrated by the acellular (hypoxanthine-xanthine oxidase) system. Interference with light detection systems was evidenced for both drugs by Lu-ACL. The clinical relevance of the antioxidant effect of rifalazil demonstrated in vitro, in particular its potential anti-inflammatory activity, requires further investigation

Polymorphonuclear Neutrophils - One of the best experts on this subject based on the ideXlab platform.

  • Interaction of Rifalazil with Oxidant-Generating Systems of Human
    2005
    Co-Authors: Polymorphonuclear Neutrophils, M. T. Labro, V. Ollivier, C. Babin-chevaye
    Abstract:

    It is well acknowledged that Ansamycins display immunosuppressive and anti-inflammatory properties in vitro and in vivo. Rifalazil, a new Ansamycin Derivative, has not been studied in the context of inflammation. In particular, there are no data on the possible interference of rifalazil with oxidant production by phagocytes. We have compared the antioxidant properties of rifalazil to those of rifampin, a drug well known in this context, by using cellular and acellular oxidant-generating systems. Oxidant production by polymorphonuclear neutrophils was measured in terms of cytochrome c reduction, lucigenin-amplified chemiluminescence (Lu-ACL), and the 2,7-dichlorofluorescin diacetate H2 (DCFDA-H2) technique (intracellular oxidant production). Rifalazil impaired O2 production in a concentration-dependent manner, with 50 % inhibitory concentrations (IC50) (concentrations which inhibit 50 % of the response) of 5.4 (30 and 60 min of incubation) and 6.4 (30 min) mg/liter, respectively, for phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. In agreement with the published fMLP-like activity of rifampin, the inhibitory effect of rifampin was significantly greater for fMLP (IC50 of 5.6 mg/liter) than for PMA (IC50 of 58 mg/liter) stimulation. Alteration of intracellular oxidant production was also observed with IC50 values similar to those obtained by the cytochrome assay. In addition, rifalazil and rifampin (>25 mg/liter) scavenged O